Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes: A Comparison of Premeal Insulin Lispro Mixtures to Once-Daily Insulin Glargine

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00191464
• Other study ID #: 6146
• Secondary ID: F3Z-MC-IOOI
• Status: Completed
• Phase: Phase 4
• First received: September 12, 2005
• Last updated: October 12, 2010
• Start date: December 2003
• Est. completion date: September 2005

Study information

• Verified date: October 2010
• Source: Eli Lilly and Company
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The primary objective of this study is to show that a prandial insulin regimen, consisting of premeal insulin lispro "mid mixture" (or a combined regimen of insulin lispro "mid mixture" and insulin lispro "low mixture") plus metformin will result in significantly better overall glycemic control (lower HbA1c) at endpoint than once-daily insulin glargine plus metformin. Insulin lispro "mid mixture" consists of 50% insulin lispro and 50% NPL. Insulin lispro "low mixture" consists of 25% insulin lispro and 75% NPL.

In a substudy of approximately 60 patients, additional data will be collected on markers associated with risk of atherosclerosis or cardiovascular disease in the context of a controlled, outpatient, high-fat test meal.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 320
• Est. completion date: September 2005
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 35 Years to 75 Years

Eligibility

Inclusion Criteria:

• Have type 2 diabetes (World Health Organization [WHO] classification

• Have used one or more of the following oral anti-hyperglycemic medications-metformin or second-generation sulfonylurea (for example, glibenclamide, glyburide, glipizide, gliclazide, glimepiride) alone or in combination with one or two insulin injections per day for at least 3 months immediately prior to entering the study. Patients using more than 2 insulin injections per day or subcutaneous insulin infusion prior to the study will not be eligible to participate.

• Have a hemoglobin A1c between 6.5% and 11%, inclusive, according to the central laboratory at Visit 1.

• Have clinically acceptable LDL-C, in the investigator's opinion, at Visit 1.

• As determined by the investigator, are capable and willing to learn how to use the insulin injection pens; comply with their prescribed diet, exercise, and medication regimen; perform self-monitoring of blood glucose; and use the patient diary as required for this protocol.

Exclusion Criteria:

• Have hypersensitivity to metformin or a known allergy to metformin hydrochloride, insulin lispro MM, insulin lispro LM, or insulin glargine, or excipients contained in these products.

• Have known metabolic or lactic acidosis.

• Have a history of renal transplantation or are currently receiving renal dialysis or have serum creatinine greater than or equal to 135 micromol/L (1.5 mg/dL) for males and greater than or equal to 110 micromol/L (1.2 mg/dL) for females.

• Have cardiac disease with functional status that is Class III or IV

• Have obvious clinical signs or symptoms of liver disease, acute or chronic hepatitis, or alanine transaminase (ALT) greater than three times the upper limit of the reference range as defined by the central laboratory.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2

Intervention

Drug:
• premeal insulin lispro mixtures

• insulin glargine

• metformin

Locations

Country	Name	City	State
Australia	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	St Leonards	New South Wales
Greece	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Thessaloniki
India	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Mumbai	Maharstra
Netherlands	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Den Helder
Poland	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Olesnica
Puerto Rico	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Ponce
United States	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon-Fri from 9AM to 5PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Lebanon	New Hampshire

Sponsors (1)

Lead Sponsor	Collaborator
Eli Lilly and Company

Countries where clinical trial is conducted

United States,  Australia,  Greece,  India,  Netherlands,  Poland,  Puerto Rico, 

References & Publications (5)

Chan JY, Leyk M, Frier BM, Tan MH. Relationship between HbA1c and hypoglycaemia in patients with type 2 diabetes treated with different insulin regimens in combination with metformin. Diabetes Metab Res Rev. 2009 Mar;25(3):224-31. doi: 10.1002/dmrr.929. — View Citation

Hirsch IB, Yuan H, Campaigne BN, Tan MH. Impact of prandial plus basal vs basal insulin on glycemic variability in type 2 diabetic patients. Endocr Pract. 2009 May-Jun;15(4):343-8. doi: 10.4158/EP08308.ORR. — View Citation

Robbins DC, Beisswenger PJ, Ceriello A, Goldberg RB, Moses RG, Pagkalos EM, Milicevic Z, Jones CA, Sarwat S, Tan MH. Mealtime 50/50 basal + prandial insulin analogue mixture with a basal insulin analogue, both plus metformin, in the achievement of target HbA1c and pre- and postprandial blood glucose levels in patients with type 2 diabetes: a multinational, 24-week, randomized, open-label, parallel-group comparison. Clin Ther. 2007 Nov;29(11):2349-64. — View Citation

Sarwat S, Ilag LL, Carey MA, Shrom DS, Heine RJ. The relationship between self-monitored blood glucose values and glycated haemoglobin in insulin-treated patients with Type 2 diabetes. Diabet Med. 2010 May;27(5):589-92. doi: 10.1111/j.1464-5491.2010.02955 — View Citation

Shrom D, Sarwat S, Ilag L, Bloomgarden ZT. Does A1c consistently reflect mean plasma glucose? J Diabetes. 2010 Jun;2(2):92-6. doi: 10.1111/j.1753-0407.2010.00066.x. Epub 2010 Jan 22. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	HbA1C
Secondary	General inflammation (hsCRP)
Secondary	High-density lipoprotein cholesterol
Secondary	Total cholesterol
Secondary	Triglycerides
Secondary	Estimates of low-density lipoprotein cholesterol
Secondary	Nuclear magnetic resonance [NMR] analysis of lipids
Secondary	Oxidized LDL
Secondary	Lipoproteins and apoproteins
Secondary	Fibrinogen
Secondary	Blood glucose levels (based on self-monitoring)
Secondary	Insulin dose
Secondary	Weight
Secondary	Frequency and incidence of hypoglycemia
Secondary	Safety
Secondary	General well-being
Secondary	Pilot two questionnaires for microvascular complications
Secondary	Coagulopathy factors [substudy]
Secondary	Surrogate measure of vascular reactivity [substudy]
Secondary	Inflammatory markers [substudy]
Secondary	Production of advanced glycation end-products [substudy]
Secondary	Generation of oxidative species [substudy]
Secondary	Lipids in various fractions [substudy]
Secondary	Retinyl ester measurements in various fractions [substudy]
Secondary	Composition of triglyceride-rich lipoproteins [substudy]
Secondary	Compartmental modeling of postprandial lipemia [substudy]
Secondary	Apolipoproteins [substudy]